Compositions and methods for the treatment of cancer

ABSTRACT

This invention relates to compositions comprising thalidomide and another anti-cancer drug which can be used in the treatment or prevention of cancer. Preferred anti-cancer drugs are topoisomerase inhibitors. A particular composition comprises thalidomide, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, and irinotecan. The invention also relates to methods of treating or preventing cancer which comprise the administration of a thalidomide and another anti-cancer drug to a patient in need of such treatment or prevention. The invention further relates to methods of reducing or avoiding adverse side effects associated with the administration of chemotherapy or radiation therapy which comprise the administration of thalidomide to a patient in need of such reduction or avoidance.

1. FIELD OF THE INVENTION

This invention relates to pharmaceutical compositions comprisingthalidomide and an anti-cancer agent, particularly a topoisomeraseinhibitor, to methods of treating cancer, and to methods of reducing oravoiding adverse effects associated with anti-cancer agents such astopoisomerase inhibitors.

2. BACKGROUND OF THE INVENTION

The incidence of cancer continues to climb as the general populationages, as new cancers develop, and as susceptible populations (e.g.,people infected with AIDS) grow. A tremendous demand therefore existsfor new methods and compositions that can be used to treat patients withcancer.

2.1. Pathobiology of Cancer

Cancer is characterized primarily by an increase in the number ofabnormal cells derived from a given normal tissue, invasion of adjacenttissues by these abnormal cells, or lymphatic or blood-bome spread ofmalignant cells to regional lymph nodes and to distant sites(metastasis). Clinical data and molecular biologic studies indicate thatcancer is a multistep process that begins with minor preneoplasticchanges, which may under certain conditions progress to neoplasia.

Pre-malignant abnormal cell growth is exemplified by hyperplasia,metaplasia, or most particularly, dysplasia (for review of such abnormalgrowth conditions, see Robbins and Angell, 1976, Basic Pathology, 2dEd., W.B. Saunders Co., Philadelphia, pp. 68-79). Hyperplasia is a formof controlled cell proliferation involving an increase in cell number ina tissue or organ, without significant alteration in structure orfunction. As but one example, endometrial hyperplasia often precedesendometrial cancer. Metaplasia is a form of controlled cell growth inwhich one type of adult or fully differentiated cell substitutes foranother type of adult cell. Metaplasia can occur in epithelial orconnective tissue cells. Atypical metaplasia involves a somewhatdisorderly metaplastic epithelium. Dysplasia is frequently a forerunnerof cancer, and is found mainly in the epithelia; it is the mostdisorderly form of non-neoplastic cell growth, involving a loss inindividual cell uniformity and in the architectural orientation ofcells. Dysplastic cells often have abnormally large, deeply stainednuclei, and exhibit pleomorphism. Dysplasia characteristically occurswhere there exists chronic irritation or inflammation, and is oftenfound in the cervix, respiratory passages, oral cavity, and gallbladder.

The neoplastic lesion may evolve clonally and develop an increasingcapacity for invasion, growth, metastasis, and heterogeneity, especiallyunder conditions in which the neoplastic cells escape the host's immunesurveillance. Roitt, I., Brostoff, J and Kale, D., Immunology,17.1-17.12 (3rd ed., Mosby, St. Louis: 1993).

Descriptions of only a few types of cancers are provided below.Characteristics of other types of cancers are well known to medicalpractitioners, and are described in the medical literature.

2.2. AIDS-Related Non-Hodgkin's Lymphoma

AIDS has been closely associated with a variety of cancers. Further, thetypes of malignancies and their incidence rates are increasing as thedevelopment of effective antiretroviral therapies and prophylaxisagainst opportunistic infections leads to prolonged survival in theimmunodeficient state for AIDS patients. Karp and Broder, Cancer Res.51:4747-4756 (1991). AIDS-related non-Hodgkin's lymphoma is a veryaggressive disease with a very high incidence of central nervous systeminvolvement. Since its discovery in 1981, the incidence of AIDS-relatednon-Hodgkin's lymphoma has reportedly increased. One reason for such anobservation is that patients infected with the AIDS virus now livelonger than they used to.

2.3. Primary and Metastatic CNS Tumors

The incidence of primary and metastatic brain tumors is also increasingin the United States. Unfortunately, the arsenal of chemotherapeuticsfor these types of cancers is minimal, while the need for suchtherapeutics is high.

Glioblastoma multiform and other primary and metastatic central nervoussystem tumors are devastating malignancies. The treatment of thesetumors include surgery, radiation therapy and treatment with agents suchas the nitrosourea BCNU. Other chemotherapeutic agents utilized includeprocarbazine, vincristine, hydroxyurea and cisplatin. But even when allthree modalities (surgery, radiation therapy and chemotherapy) areutilized, the average survival of patients with central nervous systemmalignancies is only about 57 weeks. Clearly, new treatment approachesare needed both for patients with newly diagnosed primary and metastaticcentral nervous system tumors, as well as for patients with such tumorswhich are refractory to the above modalities.

2.4. Breast, Lung, Bladder and Prostate Cancers

In the United States, the cumulative risk of developing breast cancer isreportedly about 10.2 percent. The Merck Manual 1815 (16^(th) ed. 1992).The treatment for early breast cancer is surgery, with or withoutradiation therapy, or surgery, with or without radiation therapy, pluschemotherapy and/or hormonal therapy. Current chemotherapy for patientswith primary or metastatic breast cancer includes treatment withcyclophosphamide, methotrexate, doxorubicin, 5-fluorouracil, cisplatin,vinblastine, taxol, taxotere, mitomycin C and occasionally other agents.Unfortunately, even with these agents, almost all women who developmetastatic breast cancer succumb to their disease. One particular placethat metastatic breast cancer does metastasize to is the central nervoussystem. When central nervous system metastases do occur, the usualtreatment is surgery (for a solitary metastasis) or radiation, orsurgery plus radiation therapy.

Lung cancer is reportedly the leading cause of cancer death in men andwomen. The Merck Manual 731 (16^(th) ed. 1992). A variety of causesexist, but cigarette smoking accounts for greater than 90 percent ofreported cases in men and greater than 70 percent of reported cases inwomen. Id.

Most patients with lung cancer present a tumor that has alreadymetastasized to a variety of organs, including lung, liver, adrenalgland and other organs. Treatment of metastatic lung cancer is not yetstandardized. Ihde, D. C., The New England Journal of Medicine327:1434-1441 (1992). However, chemotherapy regimens that are utilizedinclude treatment with cisplatin plus etoposide, combinations ofcyclophosphamide plus doxorubicin plus cisplatin, and single agentsalone or in combination, including ifosfamide, teniposide, vindesine,carboplatin, vincristine, taxol, nitrogen mustard, methotrexate,hexamethylmelamine and others. Despite these chemotherapeutic regimensthe average patient with metastatic lung cancer still only survives 7-12months. One particular troublesome place for metastases of lung canceris the central nervous system. The treatment for central nervous systemmetastases includes surgery (to remove a solitary lesion), radiationtherapy, or a combination of both.

Each year about 50,000 new cases of bladder cancer are reported in theUnited States. The Merck Manual 1749 (16^(th) ed. 1992). Although atpresentation the disease is usually localized, most patients developdistant metastatic disease. The most recent advances have been in thearea of chemotherapy for patients with such metastatic disease. Oneeffective regimen is called the MVAC regimen. It consists of treatmentwith methotrexate plus vinblastine plus adriamycin (doxorubicin) pluscisplatin. Although the response rate is high to this chemotherapeuticregimen, medical oncologists are noting that one place the patients failis with metastases to the central nervous system.

It is estimated that more than 120,000 men will be diagnosed withprostate cancer this year. The Merck Manual 1750 (16^(th) ed. 1992). Themost common sites of metastases in patients with prostate cancer are thebone and lymph nodes. The bone metastases are particularly bothersome inthat they can create intense pain for the patient. The current treatmentfor metastatic prostate cancer includes treatment with flutamide,leuprolide, diethylstilbestrol, and other hormonal manipulations, aswell as chemotherapy (doxorubicin, estramustine phosphate, vinblastine,suramin, cisplatin, and others). Unfortunately, none of these agents areconsistently helpful in the disease. In addition, as patients withprostate cancer live longer with their malignancy, they will most likelydevelop a higher incidence of metastases to the central nervous system(including the spinal cord).

2.5. Esophageal Cancer

Several years ago, carcinoma of the esophagus reportedly representedonly about six percent of all cancers of the gastrointestinal tract;however, it reportedly caused a disproportionate number of cancerdeaths. Boring, C. C., et al., CA Cancer J. Clin. 43:7 (1993). Thesecancers usually arise from the epithelial layer of the esophagus and areeither squamous cell carcinomas or adenocarcinomas. Overall, the 5 yearsurvival is about five percent.

2.6. Leukemia

Leukemia refers to malignant neoplasms of the blood-forming tissues.Although viruses reportedly cause several forms of leukemia in animals,causes of leukemia in humans are to a large extend unknown. The MerckManual 1233 (16^(th) ed. 1992). Transformation to malignancy typicallyoccurs in a single cell through two or more steps with subsequentproliferation and clonal expansion. In some leukemias, specificchromosomal translocations have been identified with consistent leukemiccell morphology and special clinical features (e.g., translocations of 9and 22 in chronic myelocytic leukemia, and of 15 and 17 in acutepromyelocytic leukemia). Acute leukemias are predominantlyundifferentiated cell populations and chronic leukemias more mature cellforms.

Acute leukemias are divided into lymphoblastic (ALL) andnon-lymphoblastic (ANLL) types. They may be further subdivided by theirmorphologic and cytochemical appearance according to theFrench-American-British (FAB) classification or according to their typeand degree of differentiation. The use of specific B- and T-cell andmyeloid-antigen monoclonal antibodies are most helpful forclassification. ALL is predominantly a childhood disease which isestablished by laboratory findings and bone marrow examination. ANLL,also known as acute myeloblastic leukemia (AML), occurs at all ages andis the more common acute leukemia among adults; it is the form usuallyassociated with irradiation as a causative agent.

Chronic leukemias are described as being lymphocytic (CLL) or myelocytic(CML). CLL is characterized by the appearance of mature lymphocytes inblood, bone marrow, and lymphoid organs. The hallmark of CLL issustained, absolute lymphocytosis (>5,000/μL) and an increase oflymphocytes in the bone marrow. Most CLL patients also have clonalexpansion of lymphocytes with B-cell characteristics. CLL is a diseaseof older persons. In CML, the characteristic feature is the predominanceof granulocytic cells of all stages of differentiation in blood, bonemarrow, liver, spleen, and other organs. In the symptomatic patient atdiagnosis the total WBC count is usually about 200,000/μL, but may reach1,000,000/μL. CML is relatively easy to diagnose because of the presenceof the Philadelphia chromosome.

The very nature of hematopoietic cancer necessitates using systemicchemotherapy as the primary treatment modality, and radiation therapymay be used as an adjunct to treat local accumulations of leukemiccells. Surgery is rarely indicated as a primary treatment modality, butmay be used in managing some complications. Bone marrow transplantationfrom an HLA-matched sibling is sometimes indicated.

2.7. Colorectal Cancers

In 1999, the incidence of colorectal cancer in the United States was129,400 cases. In Western countries, cancers of the colon and rectumaccount for more new cases of cancer than those of any other anatomicsite except the lung. The Merck Manual 852 (16^(th) ed. 1992). Mostcolorectal cancers are adenocarcinomas.

Despite the enormous number of deaths attributed to colorectal cancers,their specific mechanism remains unknown. It is known, however, thatcancers of the colon and rectum spread in at least five ways: directedextension through the bowel wall; hematogenous metastases; regionallymph node metastases; perineural spread; and intraluminal metastases.Id.

Primary treatment of colorectal cancers typically includes surgery. Manypatients, however, must also be treated with a combination of radiationand chemotherapy. As of 1992, the most effective chemotherapy regimeconsisted of the administration of 5-fluorouracil (5FU) and methyl-CCNU.Id.

2.8. Topoisomerase Inhibitors

Topoisomerases are enzymes that catalyze the relaxation of negativelysupercoiled deoxyribonucleic acid (DNA). The process they catalyze isbelieved to comprise three steps: cleavage of one or both strands of asupercoiled DNA; passage of a segment of DNA through the break that isformed; and resealing of the break. Type I topoisomerases cleave onestrand of DNA; type II topoisomerases cleave both strands. Stryer, L.,Biochemistry 662-663 (3^(rd) ed., 1988).

Because supercoiled double-stranded DNA must be unwound before processessuch as replication, recombination, and transcription can occur,inhibition of the unwinding process can have dramatic consequences. Forexample, compounds that prevent or slow topoisomerase activity can beused to prevent cell growth and/or cause cell death. Such compounds,which are referred to as “topoisomerase inhibitors,” have thus shownpromise in the treatment of various types of cancer. Camptothecin andits analogues are examples of topoisomerase inhibitors that exert theireffect by stabilizing DNA-topoisomerase I complexes, thereby leaving anirreversible break in the double-stranded DNA with which they areassociated. Avgeropoulos, N. G., and Batchelor, T. T., The Oncologist4:209-224 (1999).

A specific camptothecin analogue is irinotecan (also referred to asCPT-11), which is chemically named(4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidino-piperidino)carbonyl-oxy]1H-pyranol-[3′,4′:6,7]indolizinol[1,2-b]quinoline-3,14-(4H,12H)dioneand is described in U.S. Pat. No. 4,604,463. The hydrochloridetrihydrate of irinotecan is sold under the tradename CAMPTOSAR®, and isindicated in the United States for the treatment of patients withmetastatic carcinoma of the colon or rectum that recurred or progressedfollowing 5-fluorouracil based therapy. Physicians' Desk Reference,2412-2418 (54^(th) ed., 2000). It has also recently been approved in theUnited States as a first-line therapy to treat patients with metasticcolorectal cancer in combination with 5-fluorouracil and leucovorin.Irinotecan has also reportedly been used to treat other cancers, such asmalignant gliomas and NSCLC. See, e.g., Avgeropoulos, N. G., andBatchelor, T. T., The Oncologist 4:209-224 (1999).

Like other topoisomerase inhibitors, irinotecan and its metabolites(e.g., SN-38) have numerous adverse effects. Examples of such adverseeffects include, but are not limited to, early and late-formingdiarrhea, nausea, vomiting, anorexia, constipation, flatulence,leukopenia, anemia, neutropenia, asthenia, abdominal cramping, fever,pain, loss of body weight, dehydration, alopecia, dyspnea, insomnia, anddizziness. See, e.g., Physicians' Desk Reference, 2415 (54^(th) ed.,2000). The mechanisms by which these undesired effects occur are notwell understood, but are believed to be different. In particular, theearly and late-forms of diarrhea typically experienced by patients arereportedly mediated by different mechanisms. Id. But whatever theircause, the severity of one or more of their adverse effects limits theamount of topoisomerase inhibitors that can be administered to patients.The effectiveness of topoisomerase inhibitors such as irinotecan isconsequently limited not only by their ability to inhibit topoisomeraseactivity, but also by the severity and nature of their adverse effects.

Attempts have been made to alleviate adverse effects associated withirinotecan. For example, loperamide and the combination of loperamideand acetorphan have reportedly been administered to patients in aneffort to reduce delayed-onset diarrhea. Rothenberg, M. L., Annals ofOncology 8:837-855 (1997). Unfortunately, these attempts met withlimited success. Id.

2.9. Thalidomide

Thalidomide is a racemic compound sold under the tradename THALOMID® andchemically named α-(N-phthalimido)glutarimide or2-(2,6-dioxo-3-piperidinyl)-1H-isoindole-1,3(2H)-dione. Thalidomide wasoriginally developed in the 1950's to treat morning sickness, but due toits tetragenic effects was withdrawn from use. Thalidomide is nowindicated in the United States for the acute treatment of the cutaneousmanifestations of erythema nodosum leprosum. Physicians' Desk Reference,911-916 (54^(th) ed., 2000). Because its administration to pregnantwomen can cause birth defects, the sale of thalidomide is strictlycontrolled. Id.

In addition to treating symptoms of leprosy, thalidomide has reportedlybeen used to treat chronic graft-vs-host disease, rheumatoid arthritis,sarcoidosis, several inflammatory skin diseases, and inflammatory boweldisease. See generally, Koch, H. P., Prog. Med. Chem. 22:165-242 (1985).See also, Moller, D. R., et al., J. Immunol. 159:5157-5161 (1997);Vasiliauskas, E. A., et al., Gastroenterology 117:1278-1287 (1999); andEhrenpreis, E. D., et al., Gastroenterology 117:1271-1277 (1999). It hasfurther been alleged that thalidomide can be combined with other drugsto treat iscehemia/reperfusion associated with coronary and cerebralocclusion. See U.S. Pat. No. 5,643,915, which is incorporated herein byreference.

Thalidomide has also reportedly been clinically investigated in thetreatment of specific types of cancers. These include refractorymultiple myeloma, brain, melanoma, breast, colon, mesothelioma, andrenal cell carcinoma. See, e.g., Singhal, S., et al., New England J.Med. 341(21):1565-1571 (1999); and Marx, G. M., et al., Proc. Am. Soc.Clin. Oncology 18:454a (1999). It has further been reported thatthalidomide can be used to prevent the development of chroniccardiomyopathy in rats caused by doxorubicin. Costa, P. T., et al.,Blood 92(10:suppl. 1):235b (1998). Other reports concerning the use ofthalidomide in the treatment of specific cancers include its combinationwith carboplatin in the treatment of glioblastoma multiforme. McCann,J., Drug Topics 41-42 (Jun. 21, 1999). Thalidomide has reportedly alsobeen used as an antiemetic during the treatment of astrocytoma. Zwart,D., Arzneim.-Forsch. 16(12):1688-1689 (1966).

If there is a general mechanism by which thalidomide aids in thetreatment of some cancers, its nature remains unclear. See, e.g.,Moreira, A. L., et al., J. Expr. Med. 177:1675-1680 (1993); McHugh, S.M., et al., Clin. Exper. Immunol. 99:160-167 (1995); and Moller, D. R.,et al., J. Immunol. 159:5157-5161 (1997). It has been reported, however,that thalidomide is an antiangiogenic agent that can suppress tumornecrosis factor α (TNF-α) and interleukin 12 (IL-12) production. See,e.g., Moller, D. R., et al., J. Immunol. 159:5157-5161 (1997); Moreira,A. L., et al., J. Exp. Med. 177:1675-1680 (1993); U.S. Pat. Nos.5,593,990, 5,629,327, and 5,712,291 to D'Amato and U.S. Pat. No.5,385,901 to Kaplan. And in vitro studies suggest that thalidomideaffects the production of a variety of other proteins. See, e.g.,McHugh, S. M., et al., Clin. Exp. Immunol. 99:160-167 (1995).Thalidomide may also affect mechanisms related to epithelial orendothelial function or growth. D'amato M., et al., Proc. Natl. Acad.Sci. 91:4082-4085(1994).

Given the great need for an effective and safe treatment of cancer,there continues to be an extensive amount of research on new drugs orways of improving existing therapies. This invention addresses the needfor a safe and effective cancer treatment.

3. SUMMARY OF THE INVENTION

This invention is directed to pharmaceutical compositions,pharmaceutical dosage forms, kits, methods of treating or preventingcancer, methods of reducing or avoiding adverse effects associated withchemotherapy and radiation therapy, and methods of improving thetolerance of patients to chemotherapy and radiation treatment.

A first embodiment of the invention encompasses a method of treatingprimary and/or metastatic cancer, which comprises administering to apatient in need of such treatment a therapeutically effective amount ofa topoisomerase inhibitor, or a pharmaceutically acceptable prodrug,salt, solvate, hydrate, or clathrate thereof, and a therapeuticallyeffective amount of thalidomide, or a pharmaceutically acceptableprodrug, salt, solvate, hydrate, or clathrate thereof.

Specific examples of cancers that can be treated by this method include,but are not limited to, cancer of the head, neck, eye, mouth, throat,esophagus, chest, bone, lung, colon, rectum, stomach, prostate, breast,ovaries, kidney, liver, pancreas, and brain. A specific cancer that canbe treated by this method is metastatic colorectal cancer.

A second embodiment of the invention encompasses a method of increasingthe dosage of a topoisomerase inhibitor that can be safely andeffectively administered to a patient, which comprises administering toa patient in need of such an increased dosage an amount of thalidomide,or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, orclathrate thereof, that is sufficient to reduce a dose-limiting adverseeffect associated with the topoisomerase inhibitor. In a preferredmethod of this embodiment, thalidomide is administered orally and dailyin an amount of from about 1 to about 2000 mg, preferably from about 50to about 1000 mg, more preferably from about 100 to 750 mg, and mostpreferably from about 200 to about 500 mg.

Examples of dose-limiting adverse effects associated with topoisomeraseinhibitors include, but are not limited to: gastrointestinal toxicitysuch as, but not limited to, early and late-forming diarrhea andflatulence; nausea; vomiting; anorexia; leukopenia; anemia; neutropenia;asthenia; abdominal cramping; fever; pain; loss of body weight;dehydration; alopecia; dyspnea; insomnia; dizziness, mucositis,xerostomia, and kidney failure. Specific dose-limiting adverse effectsare early-forming diarrhea and late-forming diarrhea.

A third embodiment of the invention encompasses a method of reducing orpreventing an adverse effect associated with chemotherapy or radiationtherapy, which comprises administering to a patient in need of suchtreatment or prevention an amount of thalidomide, or a pharmaceuticallyacceptable prodrug, salt, solvate, hydrate, or clathrate thereof, thatis sufficient to reduce an adverse effect associated with thechemotherapy or radiation therapy. This embodiment includes the use ofthalidomide to protect against or treat an adverse effect associatedwith the use of chemotherapy or radiation therapy. The use of thethalidomide in this embodiment encompasses raising a patient's tolerancefor chemotherapy or radiation therapy. In a preferred method of thisembodiment, thalidomide is administered orally and daily in an amount offrom about 1 to about 2000 mg, preferably from about 50 to about 1000mg, more preferably from about 100 to 750 mg, and most preferably fromabout 200 to about 500 mg.

Examples of adverse effects associated with chemotherapy and radiationtherapy include, but are not limited to: gastrointestinal toxicity suchas, but not limited to, early and late-forming diarrhea and flatulence;nausea; vomiting; anorexia; leukopenia; anemia; neutropenia; asthenia;abdominal cramping; fever; pain; loss of body weight; dehydration;alopecia; dyspnea; insomnia; dizziness, mucositis, xerostomia, andkidney failure.

A fourth embodiment of the invention encompasses a method of increasingthe therapeutic efficacy of a topoisomerase inhibitor which comprisesadministering to a patient in need of such increased therapeuticefficacy an amount of thalidomide, or a pharmaceutically acceptableprodrug, salt, solvate, hydrate, or clathrate thereof, that issufficient to increase the therapeutic efficacy of the topoisomeraseinhibitor.

A fifth embodiment of the invention encompasses a pharmaceuticalcomposition comprising a topoisomerase inhibitor, or a pharmaceuticallyacceptable prodrug, salt, solvate, hydrate, or clathrate thereof, andthalidomide, or a pharmaceutically acceptable prodrug, salt, solvate,hydrate, or clathrate thereof.

A sixth embodiment of the invention encompasses a dosage form comprisinga topoisomerase inhibitor, or a pharmaceutically acceptable prodrug,salt, solvate, hydrate, or clathrate thereof, and thalidomide, or apharmaceutically acceptable prodrug, salt, solvate, hydrate, orclathrate thereof.

A seventh embodiment of the invention encompasses a kit for use in thetreatment or prevention of cancer which comprises a parenteral dosageform of irinotecan, or a pharmaceutically acceptable prodrug, salt,solvate, hydrate, or clathrate thereof, and an oral dosage form ofthalidomide, or a pharmaceutically acceptable prodrug, salt, solvate,hydrate, or clathrate thereof.

Examples of topoisomerase inhibitors that can be used in the methods,compositions, and kits of the invention include, but are not limited to,camptothecin, iriniotecan, SN-38, topotecan, 9-aminocamptothecin,GG-211, DX-8951f, saintopin, UCE6, UCE1022, TAN-1518A, TAN-1518B,KT6006, KT6528, ED-110, NB-506, ED-110, NB-506, rebeccamycin, bulgarein,Hoescht dye 33342, Hoechst dye 33258, nitidine, fagaronine,epiberberine, coralyne, beta-lapachone, BC-4-1, IST-622, rubitecan,pyrazoloacridine, XR-5000, and pharmaceutically acceptable prodrugs,salts, solvates, clathrates, hydrates, and metabolites thereof.Preferred topoisomerase inhibitors include, but are not limited to,irinotecan, SN-38, and pharmaceutically acceptable prodrugs, salts,solvates, hydrates, and clathrates thereof. In certain embodiments, thetopoisomerase inhibitor is other than irinotecan.

3.1. Definitions

As used herein, the term “cancer” includes but is not limited to solidtumors and blood born tumors. The term cancer refers to disease of skintissues, organs, bone, cartilage, blood and vessels. The inventionencompasses the treatment of various types of cancer including but notlimited to cancer of the head, neck, eye, mouth, throat, esophagus,chest, bone, lung, colon, rectum, stomach, prostate, breast, ovaries,kidney, liver, pancreas, and brain. The term “cancer” furtherencompasses primary and metastatic cancers, unless otherwise indicated.

As used herein to describe a compound or chemical moiety, the term“derivative” means a compound or chemical moiety wherein the degree ofsaturation of at least one bond has been changed (e.g., a single bondhas been changed to a double or triple bond) or wherein at least onehydrogen atom is replaced with a different atom or a chemical moiety.Examples of different atoms and chemical moieties include, but are notlimited to, halogen, oxygen, nitrogen, sulfur, hydroxy, methoxy, alkyl,amine, amide, ketone, and aldehyde.

As used herein, the term “prodrug” means a derivative of a compound thatcan hydrolyze, oxidize, or otherwise react under biological conditions(in vitro or in vivo) to provide the compound. Examples of prodrugsinclude, but are not limited to, derivatives of topoisomerase inhibitorsor thalidomide that comprise biohydrolyzable moieties such asbiohydrolyzable amides, biohydrolyzable esters, biohydrolyzablecarbamates, biohydrolyzable carbonates, and biohydrolyzable ureides.

As used herein, the terms “biohydrolyzable carbamate,” “biohydrolyzablecarbonate,” and “biohydrolyzable ureide” mean a carbamate, carbonate, orureide, respectively, of a compound that either: 1) does not interferewith the biological activity of the compound but can confer upon thatcompound advantageous properties in vivo, such as uptake, duration ofaction, or onset of action; or 2) is biologically inactive but isconverted in vivo to the biologically active compound. Examples ofbiohydrolyzable carbamates include, but are not limited to, loweralkylamines, substituted ethylenediamines, aminoacids,hydroxyalkylamines, heterocyclic and heteroaromatic amines, andpolyether amines.

As used herein, the term “biohydrolyzable ester” means an ester of acompound that either: 1) does not interfere with the biological activityof the compound but can confer upon that compound advantageousproperties in vivo, such as uptake, duration of action, or onset ofaction; or 2) is biologically inactive but is converted in vivo to thebiologically active compound. Examples of biohydrolyzable estersinclude, but are not limited to, lower alkyl esters, alkoxyacyloxyesters, alkyl acylamino alkyl esters, and choline esters.

As used herein, the term “biohydrolyzable amide” means an amide of acompound that either: 1) does not interfere with the biological activityof the compound but can confer upon that compound advantageousproperties in vivo, such as uptake, duration of action, or onset ofaction; or 2) is biologically inactive but is converted in vivo to thebiologically active compound. Examples of biohydrolyzable amidesinclude, but are not limited to, lower alkyl amides, α-amino acidamides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.

As used herein, the term “pure diastereomer” means a composition thatcomprises one diastereomer of a compound and is substantially free ofother diastereomers of the compound. A typically pure diastereomer is acompound comprising greater than about 80% by weight of one diastereomerof a compound and less than about 20% by weight of other diastereomersof the compound, more preferably greater than about 90% by weight of onediastereomer of a compound and less than about 10% by weight of otherdiastereomers of the compound, even more preferably greater than about95% by weight of one diastereomer of a compound and less than about 5%by weight of other diastereomers of the compound, and most preferablygreater than about 99% by weight of one diastereomer of a compound andless than about 1% by weight of other diastereomers of the compound.

As used herein, the terms “optically pure,” “pure enantiomer,” and“optically pure enantiomer” mean a composition that comprises oneenantiomer of a compound and is substantially free of the oppositeenantiomer of the compound. A typical optically pure enantiomers is acomposition comprising greater than about 80% by weight of oneenantiomer of a compound and less than about 20% by weight of theopposite enantiomer of the compound, more preferably greater than about90% by weight of one enantiomer of a compound and less than about 10% byweight of the opposite enantiomer of the compound, even more preferablygreater than about 95% by weight of one enantiomer of a compound andless than about 5% by weight of the opposite enantiomer of the compound,and most preferably greater than about 99% by weight of one enantiomerof a compound and less than about 1% by weight of the oppositeenantiomer of the compound.

4. DETAILED DESCRIPTION OF THE INVENTION

This invention encompasses pharmaceutical compositions, pharmaceuticaldosage forms, kits, methods of treating diseases or conditions such ascancer, methods of preventing metastases, methods of improving thetherapeutic profile of anti-cancer drugs, and methods of reducing oravoiding adverse effects associated with chemotherapy and radiationtherapy.

This invention is based, in part, on the ability of thalidomide to: (1)treat cancer; (2) improve the efficacy or tolerability of otherchemotherapeutic or radiation therapies for cancer, or; (3) lessen theseverity of certain dose-limiting toxicities of other anti-cancer drugs.Embodiments of the invention include a method of treating or preventingcancer which comprises the administration of thalidomide, or aderivative, analogue, pharmaceutically acceptable prodrug, salt,solvate, hydrate, or clathrate thereof, in combination with at least oneother anti-cancer drug to a patient. Another embodiment of the inventionencompasses a method of reducing or avoiding adverse effects associatedwith an anti-cancer drug, which comprises administering thalidomide, ora derivative, analogue, pharmaceutically acceptable prodrug, salt,solvate, hydrate, or clathrate thereof to a patient. Examples of otheranti-cancer drugs that can be used in methods of the invention include,but are not limited to, taxol (paclitaxel), taxotere (docetaxel),doxorubicin, cisplatin, topoisomerase inhibitors, and other drugsdescribed herein (e.g., those described below in Section 4.1.1.). In oneembodiment, the most preferred anti-cancer drugs are topoisomeraseinhibitors. Other embodiments of the invention encompass pharmaceuticalcompositions, pharmaceutical dosage forms, and kits comprisingthalidomide, or a derivative, analogue, pharmaceutically acceptableprodrug, salt, solvate, hydrate, or clathrate thereof, and at least oneother anti-cancer drug.

This invention further encompasses methods of: 1) allowing thecompletion of chemotherapy in a greater percentage of patients; 2)avoiding deterioration of patients' nutritional status secondary togastrointestinal toxicity; and 3) improving the overall quality ofpatients' life during chemotherapy.

Preferred embodiments of the invention are based on the unique abilityof thalidomide to improve the overall therapeutic profile oftopoisomerase inhibitors when used in the treatment or prevention ofvarious primary or metastatic cancers. For example, thalidomide as usedin this invention can improve the efficacy of topoisomerase inhibitorsat their common or approved doses. Thalidomide can further be used incombination with lower doses of topoisomerase inhibitors to reduce oravoid adverse affects associated with them while maintaining theirefficacy. Thalidomide can also be used in methods of this invention toreduce or avoid adverse effects that are associated with theadministration of topoisomerase inhibitors. Indeed, a preferred use ofthalidomide is to reduce or avoid intolerance of topoisomeraseinhibitors so that they can be used in greater amounts in the treatmentof cancer. And a specific embodiment of the invention encompasses theuse of thalidomide to reduce or avoid gastrointestinal toxicity causedby topoisomerase inhibitors. In short, this invention encompassestherapeutic effects that result from an unexpected and unique synergybetween thalidomide and topoisomerase inhibitors. One of thesetherapeutic effects is an increased potency or efficacy of topoisomeraseinhibitor; another is a reduced toxicity or increased safety oftopoisomerase inhibitor.

Compositions of the invention include bulk drug compositions useful inthe manufacture of pharmaceutical compositions (e.g., impure ornon-sterile compositions), pharmaceutical compositions (i.e.,compositions that are suitable for administration to a patient), andindividual dosage forms. Each of the compositions and dosage forms ofthe invention comprise at least two of what are referred to herein as“active ingredients.” A first active ingredient is a topoisomeraseinhibitor, or a pharmaceutically acceptable prodrug, salt, solvate,hydrate, or clathrate thereof. A second active ingredient isthalidomide, a derivative or analogue of thalidomide, or apharmaceutically acceptable prodrug, salt, solvate, hydrate, orclathrate thereof.

Examples of topoisomerase inhibitors that can be used in the methods andcompositions of the invention include, but are not limited to:camptothecin; irinotecan; SN-38; topotecan; 9-aminocamptothecin; GG-211(GI 147211); DX-8951f; IST-622; rubitecan; pyrazoloacridine; XR-5000;saintopin; UCE6; UCE1022; TAN-1518A; TAN-1518B; KT6006; KT6528; ED-110;NB-506; ED-110; NB-506; and rebeccamycin; bulgarein; DNA minor groovebinders such as, but limited to, Hoescht dye 33342 and Hoechst dye33258; nitidine; fagaronine; epiberberine; coralyne; beta-lapachone;BC-4-1; and pharmaceutically acceptable salts, solvates, clathrates, andprodrugs thereof. See, e.g., Rothenberg, M. L., Annals of Oncology8:837-855(1997); and Moreau, P., et al., J. Med. Chem. 41:1631-1640(1998). Examples of camptothecin derivatives that can be used inthe methods and compositions of this invention are disclosed by, forexample, U.S. Pat. Nos.: 6,043,367; 6,040,313; 5,932,588; 5,916,896;5,889,017; 5,801,167; 5,674,874; 5,658,920; 5,646,159; 5,633,260;5,604,233; 5,597,829; 5,552,154; 5,541,327; 5,525,731; 5,468,754;5,447,936; 5,446,047; 5,401,747; 5,391,745; 5,364,858; 5,340,817;5,244,903; 5,227,380; 5,225,404; 5,180,722; 5,122,606; 5,122,526;5,106,742; 5,061,800; 5,053,512; 5,049,668; 5,004,758; 4,981,968;4,943,579; 4,939,255; 4,894,456; and 4,604,463, each of which isincorporated herein by reference. Preferred topoisomerase inhibitorsinclude, but are not limited to, irinotecan, SN-38, and pharmaceuticallyacceptable salts, solvates, clathrates, and prodrugs thereof.

Many topoisomerase inhibitors comprise one or more chiral centers. Themethods and compositions of the invention encompass the use of racemicmixtures of such topoisomerase inhibitors, as well as enriched (i.e.,uneven) mixtures of their diastereomers or enantiomers, and purediastereomers or enantiomers of such inhibitors. Pure or substantiallypure diastereomers or enantiomers of topoisomerase inhibitors can beprepared by methods well known in the art. These include, but are notlimited to, resolution of chiral salts, asymmetric synthesis, or chiralchromatography. See generally, Beesley, T. E. and Scott, R. P. W.,Chiral Chromatography (John Wiley & Sons, New York: 1999); Principles ofAsymmetric Synthesis, Gawley, R. E. and Aube, J., eds. (Elsevier,Amsterdam: 1996); Advanced Asymmetric Synthesis, Stephenson, G. R., ed.(Chapman & Hall, London: 1996); and Asymmetric Synthetic Methodology,Ager, D. R. and East, M. B., eds. (CRC, Boca Raton: 1996). See also,Jacques, J., et al., Enanitiomers, Racemates and Resolutions(Wiley-Interscience, New York: 1981); Wilen, S. H., et al., Tetrahedron33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds(McGraw-Hill, NY: 1962); and Wilen, S. H., Tables of Resolving Agentsand Optical Resolutions, 268, Eliel, E.L., ed. (Univ. of Notre DamePress, Notre Dame: 1972). It is further contemplated thatpharmaceutically acceptable prodrugs of topoisomerase inhibitors be usedin the methods and compositions of the invention. Physiologically activemetabolites of topoisomerase inhibitors disclosed herein as well asthose known in the art can also be used in the methods and compositionsof the invention. An example of a physiologically active metabolite of atopoisomerase inhibitor is SN-38, which is a metabolite of irinotecan.

Thalidomide contains a chiral center, and is sold as a racemate. Themethods and compositions of the invention therefore encompass the use ofracemic thalidomide as well as optically pure enantiomers ofthalidomide. Optically pure enantiomers of thalidomide can be preparedby methods well known in the art. These include, but are not limited to,resolution of chiral salts, asymmetric synthesis, or chiralchromatography. It is further contemplated that pharmaceuticallyacceptable prodrugs, salts, solvate, clathrates and derivatives ofthalidomide be used in the methods and compositions of the invention.Examples of derivatives of thalidomide that can be used in the methodsand compositions of the invention include, but are not limited to,taglutimide, supidimide, EM-12, and those disclosed by InternationalApplication WO 94/20085, which is incorporated herein by reference.Other derivatives of thalidomide encompassed by this invention include,but are not limited to, 6-alkyl-2-[3′- or4′-nitrophthalimido]-glutarimides and 6-alkyl-3-phenylglutarimides. See,e.g., De, A. U., and Pal. D., J. Pharm. Sci. 64(2): 262-266 (1975).Preferred thalidomide derivatives are the amino analogues of thalidomidesuch as amino-thalidomide.

4.1. Methods of Treatment and Prevention

This invention encompasses methods of treating and preventing a widevariety of disease and conditions in mammals, and in humans inparticular. Although dosage forms of the invention can be used inmethods of the invention, the active ingredients disclosed herein can beadministered separately, in any appropriate form, and by any suitableroute.

Without being limited by theory, it is believed that the combined use ofa topoisomerase inhibitor and thalidomide to a patient suffering fromcancer provides a unique and unexpected synergism. In particular, andwithout being limited by theory, it is believed that thalidomide canwork in combination with a topoisomerase inhibitor to more rapidly killcancer cells, while at the same time reducing gastrointestinal (e.g.,diarrhea) and other side effects associated with chemotherapy (e.g.,with topoisomerase inhibitors) and radiation therapy.

Consequently, one embodiment of this invention encompasses methods oftreating and/or preventing of cancer. Examples of cancers that can betreated are disclosed herein and include, but are not limited to,primary and metastatic cancer of the head, neck, eye, mouth, throat,esophagus, chest, bone, lung, colon, rectum, stomach, prostate, breast,ovaries, kidney, liver, pancreas, and brain. Specific examples ofcancers that can be treated include, but are not limited to: AIDSassociated leukemia and adult T-cell leukemia lymphoma; anal carcinoma;astrocytoma; biliary tract cancer; cancer of the bladder, includingbladder carcinoma; brain cancer, including glioblastomas andmedulloblastomas; breast cancer, including breast carcinoma; cervicalcancer; choriocarcinoma; colon cancer including colorectal carcinoma;endometrial cancer; esophageal cancer; Ewing's sarcoma; gastric cancer;gestational trophoblastic carcinoma; glioma; hairy cell leukemia; headand neck carcinoma; hematological neoplasms, including acute and chroniclymphocytic and myelogeneous leukemia; hepatocellular carcinoma;Kaposi's sarcoma; kidney cancer; multiple myeloma; intraepithelialneoplasms, including Bowen's disease and Paget's disease; liver cancer;lung cancer including small cell carcinoma; lymphomas, includingHodgkin's disease, lymphocytic lymphomas, non-Hodgkin's lymphoma,Burkitt's lymphoma, diffuse large cell lymphoma, follicular mixedlymphoma, and lymphoblastic lymphoma; lymphocytic leukemia;neuroblastomas; oral cancer, including squamous cell carcinoma; ovariancancer, including those arising from epithelial cells, stromal cells,germ cells and mesenchymal cells; pancreatic cancer; prostate cancer;rectal cancer; sarcomas, including soft tissue sarcomas, leiomyosarcoma,rhabdomyosarcoma, liposcarcoma, fibrosarcoma, and osteosarcoma; skincancer, including melanoma, Kaposi's sarcoma, basal cell cancer andsquamous cell cancer; testicular cancer, including testicular carcinomaand germinal tumors (e.g., semicoma, non-seminoma[teratomas,choriocarcinomas]), stromal tumors and germ cell tumors; thyroid cancer,including thyroid adenocarcinoma and medullar carcinoma; and renalcancer including adenocarcinoma and Wilm's tumor.

The invention encompasses methods of treating of patients with primaryand metastatic cancers. It further encompasses methods of treatingpatients who have been previously treated for cancer, as well as thosewho have not previously been treated for cancer. Indeed, the methods andcompositions of this invention can be used in first-line and second-linecancer treatments. In a specific embodiment of the invention, the canceris metastatic. In another specific embodiment, the patient having acancer is immunosuppressed by reason of having previously undergoneanti-cancer therapy (e.g., chemotherapy radiation). In a preferredembodiment, thalidomide is administered to a patient undergoingtopoisomerase treatment before any adverse effect or intolerance occurs.

Other embodiments of the invention include methods of increasing thedosage of a topoisomerase inhibitor that can be safely and effectivelyadministered to a patient, and methods of varying the dosage cycle usedto administer a topoisomerase inhibitor to a patient while avoidingdose-limiting toxicities.

Another embodiment of the invention described in detail encompasses amethod of reducing, treating and/or preventing adverse, or undesired,effects associated with chemotherapy and/or radiation therapy.

4.1.1. Methods of Treating and/or Preventing Cancer

The methods of treating and/or preventing cancer encompassed by thisinvention comprise administering at least two drugs (also referred toherein as “active ingredients” or “active agents”) to a patient (e.g., ahuman) suffering, or likely to suffer, from cancer: 1) an anti-cancerdrug and; 2) thalidomide, a derivative or analogue of thalidomide, or apharmaceutically acceptable salt, solvate, clathrate, hydrate, orprodrug thereof. Preferred anti-cancer drugs are topoisomeraseinhibitors, or pharmaceutically acceptable salts, solvates, clathrates,hydrates, and prodrugs thereof. The two active ingredients can beadministered concurrently, sequentially, and by the same or by differentroutes of administration. For example, one active ingredient (e.g.,thalidomide) can be administered to a patient prior to, during, or afterthe administration of the other active ingredient.

A preferred method of the invention comprises the administration of: 1)a topoisomerase inhibitor, or a pharmaceutically acceptable prodrug,salt, solvate, hydrate, or clathrate thereof; 2) thalidomide, or apharmaceutically acceptable derivative, prodrug, salt, solvate, hydrate,or clathrate thereof; and 3) radiation therapy. Administration of eachof the drugs can occur prior to, during, or after radiation therapy.

Another embodiment of the invention encompasses a method of treatingcancer which comprises the administration of at least three activeingredients simultaneously or sequentially: 1) a topoisomeraseinhibitor, or a pharmaceutically acceptable prodrug, salt, solvate,hydrate, or clathrate thereof; 2) thalidomide, or a pharmaceuticallyacceptable derivative, prodrug, salt, solvate, hydrate, or clathratethereof; and 3) an additional anti- cancer drug.

Examples of anti-cancer drugs that can be used in the variousembodiments of the invention, including pharmaceutical compositions anddosage forms and kits of the invention, include, but are not limited to:acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin;aldesleukin; altretamine; ambomycin; ametantrone acetate;aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase;asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa;bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin;bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol;chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;edatrexate; eflomithine hydrochloride; elsamitrucin; enloplatin;enpromate; epipropidine; epirubicin hydrochloride; erbulozole;esorubicin hydrochloride; estramustine; estramustine phosphate sodium;etanidazole; etoposide; etoposide phosphate; etoprine; fadrozolehydrochloride; fazarabine; fenretinide; floxuridine; fludarabinephosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; ilmofosine; interleukin II (includingrecombinant interleukin II, or rIL2), interferon alfa-2a; interferonalfa-2b; interferon alfa-n1 ; interferon alfa-n3; interferon beta-I a;interferon gamma-I b; iproplatin; irinotecan hydrochloride; lanreotideacetate; letrozole; leuprolide acetate; liarozole hydrochloride;lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol;maytansine; mechlorethamine hydrochloride; megestrol acetate;melengestrol acetate; melphalan; menogaril; mercaptopurine;methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide;mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper;mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole;nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin;pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan;piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium;porfiromycin; prednimustine; procarbazine hydrochloride; puromycin;puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol;safingol hydrochloride; semustine; simtrazene; sparfosate sodium;sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin;streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium;tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicinhydrochloride. Other anti-cancer drugs include, but are not limited to:20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TKantagonists; altretamine; ambamustine; amidox; amifostine;aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;andrographolide; angiogenesis inhibitors; antagonist D; antagonist G;antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen,prostatic carcinoma; antiestrogen; antineoplaston; antisenseoligonucleotides; aphidicolin glycinate, apoptosis gene modulators;apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; argininedeaminase; asulacrine; atamestane; atrimustine; axinastatin 1;axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatinIII derivatives; balanol; batimastat; BCR/ABL antagonists;benzochlorins; benzoylstaurosporine; beta lactam derivatives;beta-alethine; betaclamnycin B; betulinic acid; bFGF inhibitor;bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistrateneA; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2;capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRestM3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinaseinhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns;chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine;clomifene analogues; clotrimazole; collismycin A; collismycin B;combretastatin A4; combretastatin analogue; conagenin; crambescidin 816;crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B;deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;diaziquone; didemnin B; didox; diethylnorspermine;dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenylspiromustine; docetaxel; docosanol; dolasetron; doxifluridine;droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine;edelfosine; edrecolomab; eflomithine; elemene; emitefur; epirubicin;epristeride; estramustine analogue; estrogen agonists; estrogenantagonists; etanidazole; etoposide phosphate; exemestane; fadrozole;fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues;paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B 1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen binding protein; sizofiran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; itanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer. Preferred additional anti-cancer drugs are 5-fluorouraciland leucovorin. These two agents are particularly useful when used inmethods employing thalidomide and a topoisomerase inhibitor.

The magnitude of a prophylactic or therapeutic dose of each activeingredient in the acute or chronic management of cancer will typicallyvary with the specific active ingredients, the severity and type ofcancer, and the route of administration. The dose, and perhaps the dosefrequency, may also vary according to age, body weight, response, andthe past medical history of the patient. Suitable dosing regimens can bereadily selected by those skilled in the art with due consideration ofsuch factors by following, for example, dosages reported in theliterature and recommended in the Physician's Desk Reference® (54^(th)ed., 2000).

Unless otherwise indicated, the magnitude of a prophylactic ortherapeutic dose of each active ingredient used in an embodiment of theinvention will be that which is known to those in the art to be safe andeffective, or is regulatory approved.

In one embodiment of the invention, the topoisomerase inhibitoririnotecan is administered parenterally about every three weeks in anamount of from about 1 to about 1000 mg/m², preferably in an amount offrom about 25 to about 750 mg/m², more preferably in an amount of fromabout 50 to about 500 mg/m², and most preferably in an amount of fromabout 100 to about 350 mg/m². And in one embodiment of the invention,thalidomide is administered orally and daily in an amount of from about1 to about 2000 mg, preferably from about 50 to about 1000 mg, morepreferably from about 100 to 750 mg, and most preferably from about 200to about 500 mg.

As noted elsewhere herein, this invention encompasses a method ofreducing the time between therapeutically safe and effective doses ofanti-cancer drugs (e.g., topoisomerase inhibitors). Consequently, in onespecific embodiment of the invention, irinotecan is administered in acycle of less than about three weeks (e.g., about once every two weeks,about once every ten days, or about once every week). The inventionfurther allows the frequency, number, and length of anti-cancer drugdosing cycles to be increased. Thus, another specific embodiment of theinvention encompasses the administration of irinotecan for more cyclesthan are typical when it is administered alone. See, e.g., Physicians'Desk Reference, 2412-2418 (54^(th) ed., 2000). In yet another specificembodiment of the invention, irinotecan is administered for a greaternumber of cycles that would typically cause dose-limiting toxicity in apatient to whom thalidomide is not also being administered.

In a typical embodiment of the invention, a topoisomerase inhibitor isadministered by intravenous infusion over about 90 minutes every cycle.In a specific embodiment wherein the topoisomerase inhibitor isirinotecan, one cycle comprises the administration of about 125 mg/m²irinotecan on days 1, 8, 15, and 22, and then two weeks of rest. Inanother specific embodiment, each cycles comprises the administration ofabout 350 mg/m² of irinotecan, followed by three weeks of rest.Typically, the number of cycles during which a topoisomerase inhibitorsuch as irinotecan is administered to a patient will be from about 1 toabout 12 cycles, more typically from about 2 to about 10 cycles, andeven more typically from about 2 to about 8 cycles.

The dosage amounts and frequencies provided above are encompassed by theterms “therapeutically effective,” “prophylactically effective,” and“therapeutically or prophylactically effective” as used herein. Whenused in connection with an amount of a thalidomide or thalidomidederivative, these terms further encompass an amount of thalidomide orthalidomide derivative that reduces, prevents, or eliminates an adverseeffect associated with the administration of radiation or an anti-cancerdrug such as a topoisomerase inhibitor, or an amount that otherwiseimproves the efficacy of radiation therapy or of an anti-cancer drug inthe treatment or prevention of cancer.

The suitability of a particular route of administration employed for aparticular active ingredient will depend on the active ingredient itself(e.g., whether it can be administered orally without decomposing priorto entering the blood stream) and the disease being treated. Forexample, treatment of tumors on the skin or on exposed mucosal tissuemay be more effective if one or both active ingredients are administeredtopically, transdermally, or mucosally (e.g., by nasal, sublingual,buccal, rectal, or vaginal administration). Treatment of tumors withinthe body, or prevention of cancers that may spread from one part of thebody to another, may be more effective if one or both of the activeingredients are administered parenterally or orally. Similarly,parenteral administration may be preferred for the acute treatment of adisease, whereas transdermal or subcutaneous routes of administrationmay be employed for chronic treatment or prevention of a disease.

4.1.2. Methods of Increasing Anti-Cancer Drug Dosages

This invention encompasses a method of increasing the dosage of ananti-cancer drug, such as a topoisomerase inhibitor, that can be safelyand effectively administered to a patient. This method comprisesadministering to a patient (e.g., a human) thalidomide, or apharmaceutically acceptable derivative, salt, solvate, clathrate,hydrate, or prodrug thereof. Patients that can benefit by this methodare those likely to suffer from an adverse effect associated with ananti-cancer drug that is alleviated or reduced by the administration ofthalidomide, or a pharmaceutically acceptable derivative, salt, solvate,clathrate, hydrate, or prodrug thereof, and which is of such severitythat it would otherwise limit the amount of topoisomerase inhibitor thatcan be safely and effectively administered to them. Such adverse effectsare referred to herein as “dose-limiting.”

For example, adverse effects that are associated with topoisomeraseinhibitors and which can limit the amount of a topoisomerase inhibitorthat can safely and effectively be administered to a patient include,but are not limited to: gastrointestinal toxicity such as, but notlimited to, early and late-forming diarrhea and flatulence; nausea;vomiting; anorexia; leukopenia; anemia; neutropenia; asthenia; abdominalcramping; fever; pain; loss of body weight; dehydration; alopecia;dyspnea; insomnia; dizziness, mucositis, xerostomia, and kidney failure.

According to a specific method of the invention, thalidomide, or apharmaceutically acceptable derivative, salt, solvate, clathrate,hydrate, or prodrug thereof, is administered prior to, during, or aftera topoisomerase inhibitor. In one embodiment, thalidomide isadministered orally and daily in an amount of from about 1 to about 2000mg, preferably from about 50 to about 1000 mg, more preferably fromabout 100 to 750 mg, and most preferably from about 200 to about 500 mg.

4.1.3. Methods of Treating and/or Preventing Adverse Effects Associatedwith Chemotherapy and Radiation Therapy

As discussed elsewhere herein, this invention encompasses a method oftreating and/or preventing adverse effects associated with chemotherapyand/or radiation therapy, such as that administered to patients withcancer. This method comprises administering to a patient (e.g., a human)thalidomide, or a pharmaceutically acceptable derivative, salt, solvate,clathrate, hydrate, or prodrug thereof before, during, or after theoccurrence of the adverse effect.

Examples of adverse effects associated with chemotherapy and radiationtherapy that can be treated or prevented by this method include, but arenot limited to: gastrointestinal toxicity such as, but not limited to,early and late-forming diarrhea and flatulence; nausea; vomiting;anorexia; leukopenia; anemia; neutropenia; asthenia; abdominal cramping;fever; pain; loss of body weight; dehydration; alopecia; dyspnea;insomnia; dizziness, mucositis, xerostomia, and kidney failure.

According to this method, thalidomide, or a pharmaceutically acceptablederivative, salt, solvate, clathrate, hydrate, or prodrug thereof, isadministered prior to, during, or after chemotherapy or radiationtherapy. In one embodiment of this method, thalidomide is administeredprior to the administration of a topoisomerase inhibitor or radiationtherapy. In another embodiment, thalidomide is administered during orafter the administration of a topoisomerase inhibitor or radiationtherapy. In still another embodiment, thalidomide is administered atleast twice for each treatment with a topoisomerase inhibitor orradiation therapy; e.g., once during the treatment and at least oncefollowing the treatment, once prior to the treatment and once during thetreatment, once both prior to and at least once after the treatment, orcombinations thereof. Preferably, thalidomide is administered before anyadverse event or symptom occurs. Indeed, thalidomide can be administeredto a patient prior to the administration of chemotherapy and/orradiation therapy, in which case it can be considered as a protectant.

In a specific embodiment of this method, thalidomide is administered inan amount of from about 1 to about 2000 mg, preferably from about 50 toabout 1000 mg, more preferably from about 100 to 750 mg, and mostpreferably from about 200 to about 500 mg orally and daily followingradiation therapy or the administration of an anti-cancer drug such as,but not limited to, a topoisomerase inhibitor.

4.2. Pharmaceutical Compositions and Dosage Forms

Pharmaceutical compositions can be used in the preparation of individualdosage forms. Consequently, pharmaceutical compositions and dosage formsof the invention comprise the active ingredients disclosed herein (e.g.,a topoisomerase inhibitor, or a pharmaceutically acceptable prodrug,salt, solvate, hydrate, or clathrate thereof, and thalidomide, aderivative or analogue of thalidomide, or a pharmaceutically acceptableprodrug, salt, solvate, hydrate, or clathrate thereof). Pharmaceuticalcompositions and dosage forms of the invention can further comprise oneor more excipients.

Pharmaceutical compositions and dosage forms of the invention can alsocomprise one or more additional active ingredients. Examples of optionaladditional active ingredients include, but are not limited to,leucovorin, 5-flurouracil, and mixtures thereof.

Single unit dosage forms of the invention are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), or transdermal administration to a patient. Examples ofdosage forms include, but are not limited to: tablets; caplets;capsules, such as soft elastic gelatin capsules; cachets; troches;lozenges; dispersions; suppositories; ointments; cataplasms (poultices);pastes; powders; dressings; creams; plasters; solutions; patches;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; and sterile solids (e.g., crystalline or amorphous solids)that can be reconstituted to provide liquid dosage forms suitable forparenteral administration to a patient.

The composition, shape, and type of dosage forms of the invention willtypically vary depending on their use. For example, a dosage form usedin the acute treatment of a disease may contain larger amounts of one ormore of the active ingredients it comprises than a dosage form used inthe chronic treatment of the same disease. Similarly, a parenteraldosage form may contain smaller amounts of one or more of the activeingredients it comprises than an oral dosage form used to treat the samedisease. These and other ways in which specific dosage forms encompassedby this invention will vary from one another will be readily apparent tothose skilled in the art. See, e.g., Remington's PharmaceuticalSciences, 18^(th) ed., Mack Publishing, Easton Pa. (1990).

Typical pharmaceutical compositions and dosage forms comprise one ormore excipients. Suitable excipients are well known to those skilled inthe art of pharmacy, and non-limiting examples of suitable excipientsare provided herein. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art including, but not limitedto, the way in which the dosage form will be administered to a patient.For example, oral dosage forms such as tablets may contain excipientsnot suited for use in parenteral dosage forms. The suitability of aparticular excipient may also depend on the specific active ingredientsin the dosage form. For example, the decomposition of some activeingredients may be accelerated by some excipients such as lactose, orwhen exposed to water. Active ingredients that comprise primary orsecondary amines are particularly susceptible to such accelerateddecomposition. Consequently, this invention encompasses pharmaceuticalcompositions and dosage forms that contain little, if any, lactose othermono- or di-saccharides. As used herein, the term “lactose-free” meansthat the amount of lactose present, if any, is insufficient tosubstantially increase the degradation rate of an active ingredient.

Lactose-free compositions of the invention can comprise excipients thatare well known in the art and are listed, for example, in the U.S.Pharmocopia (USP) SP (XXI)/NF (XVI). In general, lactose-freecompositions comprise active ingredients, a binder/filler, and alubricant in pharmaceutically compatible and pharmaceutically acceptableamounts. Preferred lactose-free dosage forms comprise activeingredients, microcrystalline cellulose, pre-gelatinized starch, andmagnesium stearate.

This invention further encompasses anhydrous pharmaceutical compositionsand dosage forms comprising active ingredients, since water canfacilitate the degradation of some compounds. For example, the additionof water (e.g., 5%) is widely accepted in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. See, e.g., Jens T. Carstensen, Drug Stability: Principles &Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect,water and heat accelerate the decomposition of some compounds. Thus, theeffect of water on a formulation can be of great significance sincemoisture and/or humidity are commonly encountered during manufacture,handling, packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are preferablyanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The invention further encompasses pharmaceutical compositions and dosageforms that comprise one or more compounds that reduce the rate by whichan active ingredient will decompose. Such compounds, which are referredto herein as “stabilizers,” include, but are not limited to,antioxidants such as ascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients. However, typical dosage forms of the invention comprisethalidomide, a derivative or analogue of thalidomide, or apharmaceutically acceptable salt, solvate, clathrate, hydrate, orprodrug thereof in an amount of from about 1 mg to about 2000 mg, morepreferably from about 50 mg to about 1000 mg, even more preferably fromabout 100 mg to about 750 mg, and most preferably from about 200 mg toabout 500 mg. Similarly, typical dosage forms of the invention comprisea topoisomerase inhibitor or a pharmaceutically acceptable salt,solvate, clathrate, hydrate, prodrug or derivative thereof in an amountof from about 1 mg to about 1000 mg, more preferably from about 25 mg toabout 750 mg, even more preferably from about 50 mg to about 500 mg, andmost preferably from about 100 mg to about 350 mg.

4.2.1. Oral Dosage Forms

Pharmaceutical compositions of the invention that are suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets (e.g., chewable tablets), caplets, capsules,and liquids (e.g., flavored syrups). Such dosage forms containpredetermined amounts of active ingredients, and may be prepared bymethods of pharmacy well known to those skilled in the art. Seegenerally, Remington's Pharmaceutical Sciences, 18^(th) ed., MackPublishing, Easton Pa. (1990).

Typical oral dosage forms of the invention are prepared by combining theactive ingredients in an intimate admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or nonaqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided solid carriers,or both, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms of theinvention include, but are not limited to, binders, fillers,disintegrants, and lubricants. Binders suitable for use inpharmaceutical compositions and dosage forms include, but are notlimited to, corn starch, potato starch, or other starches, gelatin,natural and synthetic gums such as acacia, sodium alginate, alginicacid, other alginates, powdered tragacanth, guar gum, cellulose and itsderivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropylmethyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystallinecellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Anspecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103™and Starch 1500LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions of the invention istypically present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants are used in the compositions of the invention to providetablets that disintegrate when exposed to an aqueous environment.Tablets that contain too much disintegrant may disintegrate in storage,while those that contain too little may not disintegrate at a desiredrate or under the desired conditions. Thus, a sufficient amount ofdisintegrant that is neither too much nor too little to detrimentallyalter the release of the active ingredients should be used to form solidoral dosage forms of the invention. The amount of disintegrant usedvaries based upon the type of formulation, and is readily discernible tothose of ordinary skill in the art. Typical pharmaceutical compositionscomprise from about 0.5 to about 15 weight percent of disintegrant,preferably from about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, agar-agar,alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, other starches, pre-gelatinizedstarch, other starches, clays, other algins, other celluloses, gums, andmixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, andmixtures thereof. Additional lubricants include, for example, a syloidsilica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore,Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co.of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants are typically used in an amount of less than about 1 weightpercent of the pharmaceutical compositions or dosage forms into whichthey are incorporated.

A preferred solid oral dosage form of the invention comprisesthalidomide, anhydrous lactose, microcrystalline cellulose,polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, andgelatin.

4.2.2. Delayed Release Dosage Forms

Active ingredients of the invention can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 35 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein,, can be readily selected for usewith the active ingredients of the invention. The invention thusencompasses single unit dosage forms suitable for oral administrationsuch as, but not limited to, tablets, capsules, gelcaps, and capletsthat are adapted for controlled-release.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased patient compliance. In addition,controlled-release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and can thus affect the occurrence of side (e.g., adverse) effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

4.2.3. Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. Becausetheir administration typically bypasses patients' natural defensesagainst contaminants, parenteral dosage forms are preferably sterile orcapable of being sterilized prior to administration to a patient.Examples of parenteral dosage forms include, but are not limited to,solutions ready for injection, dry products ready to be dissolved orsuspended in a pharmaceutically acceptable vehicle for injection,suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage forms ofthe invention are well known to those skilled in the art. Examplesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms of the invention. For example, cyclodextrin andits derivatives can be used to increase the solubility of thalidomideand its derivatives. See, e.g., U.S. Pat. No. 5,134,127, which isincorporated herein by reference.

A preferred parenteral composition of the invention is intended fordilution with 5% Dextrose Injection, USP, or 0.9% Sodium ChlorideInjection, USP, prior to administration to a patient, and is an aqueoussolution that comprises irinotecan, sorbitol NF powder, and lactic acid,USP, and has a pH of from about 3.0 to about 3.8.

4.2.4. Transdermal, Topical, and Mucosal Dosage Forms

Transdermal, topical, and mucosal dosage forms of the invention include,but are not limited to, ophthalmic solutions, sprays, aerosols, creams,lotions, ointments, gels, solutions, emulsions, suspensions, or otherforms known to one of skill in the art. See, e.g., Remington'sPharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa.(1980 & 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed.,Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treatingmucosal tissues within the oral cavity can be formulated as mouthwashesor as oral gels. Further, transdermal dosage forms include “reservoirtype” or “matrix type” patches, which can be applied to the skin andworn for a specific period of time to permit the penetration of adesired amount of active ingredients.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide transdermal, topical, and mucosal dosageforms encompassed by this invention are well known to those skilled inthe pharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied. Withthat fact in mind, typical excipients include, but are not limited to,water, acetone, ethanol, ethylene glycol, propylene glycol,butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil,and mixtures thereof to form lotions, tinctures, creams, emulsions, gelsor ointments, which are non-toxic and pharmaceutically acceptable.Moisturizers or humectants can also be added to pharmaceuticalcompositions and dosage forms if desired. Examples of such additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa.(1980 & 1990).

Depending on the specific tissue to be treated, additional componentsmay be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients of the invention. For example, penetrationenhancers can be used to assist in delivering the active ingredients tothe tissue. Suitable penetration enhancers include, but are not limitedto: acetone; various alcohols such as ethanol, oleyl, andtetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such aspolyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; andvarious water-soluble or insoluble sugar esters such as Tween 80(polysorbate 80) and Span 60 (sorbitan monostearate).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, mayalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

4.2.5. Kits

Typically, active ingredients of the invention are preferably notadministered to a patient at the same time or by the same route ofadministration. This invention therefore encompasses kits which, whenused by the medical practitioner, can simplify the administration ofappropriate amounts of active ingredients to a patient.

A typical kit of the invention comprises a dosage form of an anti-cancerdrug (e.g., a. topoisomerase inhibitor) or a pharmaceutically acceptableprodrug, salt, solvate, hydrate, or clathrate thereof, and a dosage formof thalidomide, or a pharmaceutically acceptable derivative, prodrug,salt, solvate, hydrate, or clathrate thereof. Kits encompassed by thisinvention can further comprise additional active ingredients. Examplesof optional additional active ingredients include, but are not limitedto, leucovorin, 5-flurouracil, and mixtures thereof.

Kits of the invention can further comprise devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, drip bags, patches, and inhalers.

Kits of the invention can further comprise pharmaceutically acceptablevehicles that can be used to administer one or more active ingredients.For example, if an active ingredient is provided in a solid form thatmust be reconstituted for parenteral administration, the kit cancomprise a sealed container of a suitable vehicle in which the activeingredient can be dissolved to form a particulate-free sterile solutionthat is suitable for parenteral administration. Examples ofpharmaceutically acceptable vehicles include, but are not limited to:Water for Injection USP; aqueous vehicles such as, but not limited to,Sodium Chloride Injection, Ringer's Injection, Dextrose Injection,Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection;water-miscible vehicles such as, but not limited to, ethyl alcohol,polyethylene glycol, and polypropylene glycol; and non-aqueous vehiclessuch as, but not limited to, corn oil, cottonseed oil, peanut oil,sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

A specific kit of the invention comprises a solid dosage form ofthalidomide suitable for oral administration to a patient, and a liquiddosage form of irinotecan suitable for dilution and parenteraladministration to a patient. A preferred oral dosage form of thalidomidecomprises 50 mg thalidomide, anhydrous lactose, microcrystallinecellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydroussilica, and gelatin. A preferred liquid dosage form of irinotecancomprises 100 mg irinotecan hydrochloride, sorbitol NF powder, andlactic acid, USP, and has a pH of from about 3.0 to about 3.8.

Other kits encompassed by the invention will be readily apparent tothose skilled in the art, since thalidomide, irinotecan, and othertherapeutic and anti-cancer drugs or radiation therapies are well knownand/or commercially available.

5. EXAMPLES

Certain embodiments of the invention, as well as certain novel andunexpected advantages of the invention, are illustrated by the followingnon-limiting examples.

5.1. Example 1: Treatment of Colorectal Cancer

A pilot clinical trial was conducted to investigate the safety andefficacy of administering thalidomide (400 mg/day, administered atbedtime) and irinotecan (325-350 mg/m² every 21 days) to patients withmetastatic colorectal cancer. An interim analysis performed afterenrollment of the first 9 patients on this protocol (2-8 cycles ofirinotecan) revealed a remarkable absence of gastrointestinal toxicitytypically associated with irinotecan. See Table 1. All patients wereable to complete the prescribed chemotherapy regimen; only one patientrequired a 50% reduction of the irinotecan dose due to asthenia, andonly one patient required a thalidomide dose reduction by 75% due tosomnolence. Of the seven patients that could be evaluated, one went intocomplete remission, two attained partial remission, one had stabledisease, and three progressed. TABLE 1 Observed Toxicity Profile forCombination Therapy with Thalidomide and Irinotecan in 9 Patients withMetastatic Colorectal Cancer Compared with the Expected Toxicity Profileof Irinotecan Monotherapy Expected (%) Observed (N) Symptom Grade 1-4Grade 3-4 Grade 1-4 Grade 3-4 p Nausea 86.2 16.8 0 1 <0.00001 Vomiting66.8 12.5 0 0  0.00005 Diarrhea 87.8 30.6 1 0 <0.00001 (Late) Abdominal23.7 2.3 0 0 n.s colic/pain Constipation 29.9 2.0 4 0 n.s. Asthenia 75.712.2 6 0 n.s.

The p-values shown in Table 1 refer to the probability of observing thespecified number of Grade 1-4 symptoms among 9 patients, given theexpected frequencies of Grade 1-4 toxicity. Expected frequencies oftoxicity were obtained from Rothenberg, M. L., et al., J. Clin. Oncology14(4):1128-1135 (1996); Pitot, H. C., et al., J. Clin. Oncology15(8):2910-2919 (1997); and Rothenberg, M. L., et al., Cancer85(4):786-795 (1999).

The complete absence of severe (grade 3-4) gastrointestinal toxicity inthe patients used in the study is striking, statistically highlysignificant, and clinically very important.

5.2. Example 2: Alternative Treatment of Colorectal Cancer

In this study, 5FU, leucovorin, irinotecan, and thalidomide are used incombination to treat metastatic colorectal cancer. Patients withhistologically confirmed colon or rectal carcinoma are treated using sixweek cycles, which comprise the intravenous administration of 125 mg/m²of irinotecan over 90 minutes, followed by 20 mg/m² bolus administrationof leucovorin, followed by 500 mg/m² bolus administration of 5FU. Eachdrug is administered weekly ×4, followed by two weeks of rest.Thalidomide is administered daily and orally at a dose of 400 mg atbedtime. The response of each patient is assessed at the conclusion ofeach cycle using methods and criteria described herein and known tothose skilled in the art.

5.3. Example 3: Treatment of Myelodysplastic Syndromes

The efficacy of using a combination of topotecan and thalidomide inimproving the ineffective hematopoiesis of poor prognosis patients withmyelodysplastic syndromes (MDS), patients with refractory anemia withexcess blasts (RAEB) who have greater than about 15 percent blasts inthe bone marrow (BM), RAEB in transformation (RAEB-t), and patients withchronic myelomonocytic leukemia (CMMoL) are determined as set forthbelow.

The treatment comprises administering topotecan hydrochloride (Hycamtin)by intravenous infusion (1.25 mg/m² over 30 minutes) to patients(RAEB>5%) for five days every 21 days, for three cycles (each cycle is21 days). At the conclusion of the cycles, each patient is evaluated. Ifthe blasts have decreased to less than about five percent or havedecreased by half, the administration of thalidomide is begun: it isfirst administered orally at about 100 mg/day, and increased up to about300 mg as tolerated for a maximum of about one year.

If, following the three initial cycles of topotecan therapy, the blastsare still greater than five percent, two additional cycles of topotecanare administered, after which thalidomide therapy is begun. As above,thalidomide is first administered orally at about 100 mg/day, andincreased up to about 300 mg as tolerated for a maximum of about oneyear.

Frequent monitoring of peripheral blood cell counts are institutedduring the treatment, since Hycamtin should only be administered topatients with adequate bone marrow reserves, including baselineneutrophil counts of at least 1,500 cells/mm³ and platelet count of atleast 100,000/mm³. Other precautions taken during the study are wellknown to those skilled in the art.

During the therapy, apoptosis studies are performed on all bone marrowsamples using flow cytometry (TUNNEL technique) or DNA laddering (gelelectrophoresis or pulsed field electrophoresis) techniques.Proliferation studies are also performed to determine detailed cellcycle kinetics. Cytokine expression studies are also performed. Inparticular, TNF-a is measured by standard ELISA techniques on a weeklybasis, while bone marrow aspirate is studied by sorting and measuringmRNA levels using multiplex RT-PCR for a variety of cytokines includingILI-β, TNF-α, IL6, flt3 ligand, hSCF, and GM-CSF. An immunohistochemicaldetection of TNF-α and IL1-β is also performed on all biopsies.

5.4. Example 4: Treatment of Prostate Cancer

The efficacy of using a combination of docetaxel and thalidomide in thetreatment of prostate cancer is determined as described below inpatients with histologically confirmed prostate or pancreatic cancer.The efficacy of the combination is also determined with regard toprogressive disease after therapy with gemcitabine in patients withpancreatic cancer or after androgen suppression therapy in patients withmetastatic prostate cancer.

Patients who meet criteria known to those skilled in the art (e.g.,those who are not pregnant, HIV-positive, or those with active brainmetastasis) are intravenously administered docetaxel once weekly (Day 1)for a total of 24 weeks at a dose of 33 mg/M². Premedication withdexamethasone 8 mg PO Q6H×3 doses, starting 12 hours before theadministration of docetaxel is given to decrease or prevent acuteanaphylactoid reactions and to decrease the severity or delay the onsetof late-occurring fluid retention problems.

Three days prior to starting treatment with thalidomide (Day 5),subjects are initiated on a bowel regimen to minimize the occurrence ofconstipation. On week 2 (Day 8), patients first receive thalidomide,which is administered daily at bedtime in four schedules using a weeklydose-escalation design,. See, e.g., Gruber, M. L., et al., CancerInvestigation 2000; 18(suppl. 1):41 (abstract); Eisen T., CancerInvestigation 2000; 18 (suppl. 1):42 (abstract); and Figg. W., et al.,Cancer Investigation 2000; 18 (suppl. 1):81 (abstract). Three patientsare treated on the initial schedule. If no dose-limiting toxicities areobserved, three patients are treated on the next schedule. If one ofthree patients treated on a schedule develops a dose-limiting toxicity,three additional patients are treated on that schedule. If two patientstreated on a schedule develop dose-limiting toxicity, the maximumtolerated dose of thalidomide has been reached, and is defined to be theprevious schedule (or to be a does below the initial dose if twopatients develop dose-limiting toxicity on the first schedule). If onlythree patients have been treated on the previous schedule, then threeadditional patients are treated on the current one. If, at any time, thedata suggest a significant hazard to further dose escalation, doseescalation is halted pending a review of the data.

Thalidomide is given daily until progression, unacceptable toxicitydevelops, or when the subject wishes to discontinue treatment. Forsubjects who are stable and show no signs of unacceptable toxicity, themaximum daily dose of thalidomide that is given in this regime is 200mg, 400 mg, 600 mg, or 800 mg for each level shown in Table 2: TABLE 2Dose of Thalidomide (mg/day) as a Function of Week and Schedule WK 1 2 34 5 6 7 8 9 10 11 12 13 14 15 16 I 50 100 150 200 200 2000 200 200 200200 200 200 200 200 200 200 II 50 100 150 200 250 300 350 400 400 400400 400 400 400 400 400 III 50 100 150 200 250 300 350 400 450 500 550600 600 600 600 600 IV 50 100 150 200 250 300 350 400 450 500 550 600650 700 750 800

Baseline radiographic studies are done for initial tumor measurements.Chest X-ray is done to measure pulmonary metastases, and a CT scan ofthe abdomen is done for those patients with liver or other abdominalmetastases that are measurable using that modality. Baseline laboratorystudies are also performed, such as serum biochemistry, hematological,PSA (prostate patients only), CA 19-9 (pancreatic patients only),pregnancy, and binding protein studies, as known to those skilled in theart. These studies are continued during treatment to determine itseffectiveness, and to ensure the safety of each patient.

The embodiments of the invention described above are intended to bemerely exemplary, and those skilled in the art will recognize, or willbe able to ascertain using no more than routine experimentation,numerous equivalents of specific compounds, materials, and procedures.All such equivalents are considered to be within the scope of theinvention and are encompassed by the appended claims.

1-60. (canceled)
 61. A method for treating multiple myeloma in a subjectcomprising administering an amino analogue of thalidomide in combinationwith irinotecan.
 62. The method of claim 61, wherein the irinotecan is apharmaceutically acceptable salt.
 63. The method of claim 62, whereinthe pharmaceutically acceptable salt of irinotecan is a hydrochloridesalt.
 64. The method of claim 63, wherein the irinotecan hydrochloridesalt is CPT-
 11. 65. The method of claim 61, wherein the irinotecan isadministered as an oral dosage form.
 66. The method of claim 61, whereinthe amino analogue of thalidomide is administered as an oral dosageform.
 67. The method of claim 61, wherein the amino analogue ofthalidomide and irinotecan are administered sequentially.
 68. The methodof claim 67, wherein amino analogue of thalidomide and irinotecan areadministered sequentially in any order.
 69. The method of claim 1,wherein the amino analogue of thalidomide and irinotecan areadministered simultaneously.
 70. The method of claim 61, wherein thesubject has had prior chemotherapy.
 71. The method of claim 70, whereinthe prior chemotherapy comprises treatment with MP, VAD, or treatmentwith one or more alkylating agents.
 72. The method of claim 70, whereinthe prior chemotherapy comprises treatment with cyclophosphamide andetoposide, or treatment with etoposide, dexamethasone and doxorubicin.73. The method of claim 70, wherein amino analogue of thalidomide andirinotecan are administered sequentially, in any order.
 74. The methodof claim 70, wherein amino analogue of thalidomide and irinotecan areadministered simultaneously.
 75. A pharmaceutical preparation for thetreatment of multiple myeloma comprising an amino analogue ofthalidomide and irinotecan.
 76. The pharmaceutical preparation of claim75 wherein the the amino analogue of thalidomide and irinotecan areprovided in a single dosage device.
 77. The pharmaceutical preparationof claim 75 wherein the amino analogue of thalidomide and the irinotecanare provided in separate dosage devices.
 78. A method for treatingmultiple myeloma in a patient comprising administering an oral aminoanalogue of thalidomide in combination with oral irinotecan.
 79. Themethod of claim 78, wherein the irinotecan is a pharmaceuticallyacceptable salt form.
 80. The method of claim 79, wherein thepharmaceutically acceptable salt form of irinotecan is a hydrochloridesalt.
 81. The method of claim 80, wherein the irinotecan hydrochloridesalt is CPT-11.
 82. The method of claim 78, wherein the amino analogueof thalidomide and irinotecan are administered sequentially.
 83. Themethod of claim 82, where the amino analogue of thalidomide andirinotecan are administered sequentially in any order.
 84. The method ofclaim 78, wherein the amino analogue of thalidomide and irinotecan areadministered simultaneously.